US12252490B2ActiveUtilityA1
Inhibiting deubiquitinase USP25 and USP28
Est. expiryAug 9, 2038(~12.1 yrs left)· nominal 20-yr term from priority
Inventors:David Joseph GuerinJustin Andrew CaravellaHongbin LiSteven MischkeDavid RichardShawn SchillerTatiana Shelekhin
C07D 519/00C07D 471/04A61P 35/00C07D 487/08C07D 487/04
57
PatentIndex Score
0
Cited by
85
References
15
Claims
Abstract
The present disclosure relates to modulators, such as inhibitors, of at least one pathway chosen from USP28 and USP25, pharmaceutical compositions comprising the inhibitors, and methods of using the inhibitors. The modulators, such as inhibitors, of at least one pathway chosen from USP28 and USP25 can be useful in the treatment of cancers, among other ailments. The present disclosure provides compounds of Formula (I).
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound of Formula (I):
or pharmaceutically acceptable form thereof, wherein:
X is selected from N or C(R′);
R′ is selected from hydrogen, deuterium, and CH 3 ;
Y is C(R);
R is selected from hydrogen, NH 2 , and C1-C4 alkyl groups;
R 1 is selected from Rx, hydrogen, C1-C5 linear and C3-C5 branched alkyl groups, wherein the alkyl groups are optionally substituted with one or more Rx;
each Rx is selected from halogen or —OH;
R 2 is selected from hydrogen and halogen;
R 3 , R 4 , and R 4′ are each independently selected from hydrogen and C1-C4 alkyl;
R 5 is a 6- to 8-membered heterocyclic ring;
R 6 is selected from hydrogen, deuterium, halogen, C1-C4 alkyl, and —CN; and
n is 0, 1, or 2.
2. The compound of claim 1 , wherein:
X is C(R′);
R′ is selected from hydrogen and deuterium;
R is NH 2 ;
R 1 , R 2 , R 3 , R 4 , and R 4′ are hydrogen;
R 5 is a 6-membered heterocyclic ring; and
n is 0.
3. The compound of claim 1 , wherein:
X is C(R′);
R′ is selected from hydrogen and deuterium;
R is hydrogen;
R 1 is C1-C3 linear alkyl, optionally substituted with one to three Rx;
R 2 and R 3 are hydrogen;
R 4 and R 4′ are independently selected from hydrogen and CH 3 ;
R 5 is a 6-8-membered heterocyclic ring;
R 6 is selected from hydrogen, deuterium, and halogen; and
n is 0, 1, or 2.
4. The compound of claim 1 , wherein:
X is C(R′), wherein R′ is hydrogen;
R is hydrogen;
R 1 is methyl or ethyl, optionally substituted with one to three Rx;
R 2 and R 3 are hydrogen;
R 4 and R 4′ are independently selected from hydrogen and CH 3 ;
R 5 is a 6-8-membered heterocyclic ring;
R 6 is selected from hydrogen and halogen; and
n is 0, 1, or 2.
5. The compound of claim 1 , wherein:
X is C(R′);
R′ is selected from hydrogen and deuterium;
R is hydrogen;
R 1 is C3-C4 branched alkyl optionally substituted with one to three Rx;
R 2 and R 3 are hydrogen;
R 4 and R 4′ are independently selected from hydrogen and CH 3 ;
R 5 is a 6-8-membered heterocyclic ring;
R 6 is selected from hydrogen, deuterium, and halogen; and
n is 0, 1, or 2.
6. The compound of claim 1 , wherein:
X is C(R′), wherein R′ is hydrogen;
R is hydrogen;
R 1 is C3-C4 branched alkyl, optionally substituted with one to three Rx;
R 2 and R 3 are hydrogen;
R 4 and R 4′ are hydrogen;
R 5 is a 6-8-membered heterocyclic ring;
R 6 is selected from hydrogen and halogen; and
n is 0, 1, or 2.
7. The compound of claim 1 , wherein:
X is C(R′), wherein R′ is hydrogen;
R is hydrogen;
R 1 is hydrogen;
R 2 is halogen;
R 3 is hydrogen;
R 4 and R 4′ are hydrogen;
R 5 is a 6-8-membered heterocyclic ring;
R 6 is selected from hydrogen and halogen; and
n is 0, 1, or 2.
8. The compound of claim 1 , wherein:
X is C(R′), wherein R′ is hydrogen;
R is hydrogen;
R 1 is selected from hydrogen, and C1-C3 linear alkyl optionally substituted with one to three Rx;
R 2 is halogen;
R 3 is hydrogen;
R 4 and R 4′ are hydrogen;
R 5 is a 6-8-membered heterocyclic ring;
R 6 is selected from hydrogen and halogen; and
n is 0, 1, or 2.
9. The compound of claim 1 , wherein:
X is N;
R is hydrogen;
R 1 is selected from hydrogen, and C1-C3 linear alkyl optionally substituted with one to three Rx;
R 2 is hydrogen;
R 3 is hydrogen;
R 4 and R 4′ are selected from hydrogen and CH 3 ;
R 5 is a 6-8-membered heterocyclic ring;
R 6 is selected from hydrogen and halogen; and
n is 0, 1, or 2.
10. The compound of claim 1 , wherein R5 is a 6-8 membered heterocyclic ring with two nitrogens.
11. The compound of claim 1 , wherein each halogen is independently selected from F and Cl.
12. The compound of claim 1 , wherein the compound is chosen from:
Ex. #
Structure
Compound Name
1-1
N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-2,5-difluorophenethyl)-1-ethyl- 1H-pyrrolo[2,3-b]pyridine-5- carboxamide
1-2
N-(4-(piperazin-1-yl)phenethyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
1-3
1-methyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide
1-4
1-ethyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide
1-5
4-amino-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide
1-6
N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)phenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
1-7
N-(2,5-difluoro-4-(piperazin-1- yl)phenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
1-8
N-(4-(piperazin-1-yl)phenethyl)-1- (2,2,2-trifluoroethyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
1-9
N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-2,5-difluorophenethyl)-1-(2- hydroxy-2-methylpropyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
1-10
N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-3-fluorophenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
2-1
(S)-N-(2-(2,5-difluoro-4-(piperazin- 1-yl)phenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
2-2
(R)-N-(2-(2,5-difluoro-4-(piperazin- 1-yl)phenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
2-3
N-((2R)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
2-4
N-((2S)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
3-1
3-chloro-1-ethyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide
3-2
3-chloro-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide
4-1
N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-2,5-difluorophenethyl)-7-ethyl- 7H-pyrrolo[2,3-c]pyridazine-3- carboxamide
4-2
N-((2R)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3- carboxamide
4-3
N-((2S)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3- carboxamide
4-4
N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-2,5-difluorophenethyl)-5- chloro-7-ethyl-7H-pyrrolo[2,3- c]pyridazine-3-carboxamide
and;
wherein the compound is:
(a) a USP28 Inhibitor compound having an IC 50 of 0.001-10 micromolar in the Ubiquitin-Rhodamine 110 Assay for USP28;
(b) a USP25 Inhibitor compound having an IC 50 of 0.001-10 micromolar in the Ubiquitin-Rhodamine 110 Assay for USP25.
13. The compound of claim 12 , wherein the compound is
(c) a USP28 Inhibitor compound having an IC 50 of 0.001-2 micromolar in the Ubiquitin-Rhodamine 110 Assay for USP28;
(d) a USP25 Inhibitor compound having an IC 50 of 0.001-2 micromolar in the Ubiquitin-Rhodamine 110 Assay for USP25.
14. The compound of claim 1 , chosen from:
Ex. #
Structure
Compound Name
1-1
N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-y1)-2,5-difluorophenethyl)-1-ethyl- 1H-pyrrolo[2,3-b]pyridine-5- carboxamide
1-2
N-(4-(piperazin-1-yl)phenethyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
1-3
1-methyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide
1-4
1-ethyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide
1-5
4-amino-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide
1-6
N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)phenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
1-7
N-(2,5-difluoro-4-(piperazin-1- yl)phenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
1-8
N-(4-(piperazin-1-yl)phenethyl)-1- (2,2,2-trifluoroethyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
1-9
N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-2,5-difluorophenethyl)-1-(2- hydroxy-2-methylpropyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
1-10
N-(4-(3,8-diazabicyclo[3.2.1 ]octan- 3-yl)-3-fluorophenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
2-1
(S)-N-(2-(2,5-difluoro-4-(piperazin- 1-yl)phenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
2-2
(R)-N-(2-(2,5-difluoro-4-(piperazin- 1-yl)phenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide
2-3
N-((2R)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide
2-4
N-((2S)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide
3-1
3-chloro-1-ethyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide
3-2
3-chloro-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide
4-1
N-(4-(3,8-diazabicyclo[3.2.1 ]octan- 3-yl)-2,5-difluorophenethyl)-7-ethyl- 7H-pyrrolo[2,3-c]pyridazine-3- carboxamide
4-2
N-((2R)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3-carboxamide
4-3
N-((2S)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3- carboxamide
4-4
N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-y1)-2,5-difluorophenethyl)-5- chloro-7-ethyl-7H-pyrrolo[2,3- c]pyridazine-3-carboxamide
15. A composition comprising at least one compound of claim 1 , and a biologically acceptable carrier.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.